U.S. Pat. Nos. 4,046,889 and 4,105,776 to Ondetti et al discloses proline derivatives which are angiotensin converting enzyme (ACE) inhibitors and have the general formula ##STR1## wherein
R is hydroxy, NH.sub.2 or lower alkoxy;
R.sub.1 and R.sub.4 each is hydrogen, lower alkyl, phenyl or phenyl-lower alkyl;
R.sub.2 is hydrogen, lower alkyl, phenyl, substituted phenyl wherein the phenyl substituent is halo, lower alkyl or lower alkoxy, phenyl-lower alkyl, diphenyl-lower alkyl, triphenyl-lower alkyl, lower alkylthiomethyl, phenyl-lower alkylthiomethyl, lower alkanoyl-amidomethyl, ##STR2##
R.sub.3 is hydrogen, hydroxy or lower alkyl;
R.sub.5 is lower alkyl, phenyl or phenyl-lower alkyl;
R.sub.6 is lower alkyl, phenyl, substituted phenyl (wherein the phenyl substituent is halo, lower alkyl or lower alkoxy), hydroxy-lower alkyl or amino(carboxy)lower alkyl;
R.sub.7 is ##STR3##
M is O or S; m is 1 to 3; n and p each is 0 to 2.
The asterisks indicate asymmetric carbon atoms. Each of the carbons bearing a substituent R.sub.1, R.sub.3 and R.sub.4 is asymmetric when that substituent is other than hydrogen.
These patents disclose captopril.
U.S. Pat. No, 4,168,267 to Petrillo discloses phosphinylalkanoyl prolines which have the formula ##STR4## wherein
R.sub.1 is lower alkyl, phenyl or phenyl-lower alkyl;
R.sub.2 is hydrogen, phenyl-lower alkyl or a metal ion;
R.sub.3 is hydrogen or lower alkyl;
R.sub.4 is hydrogen, lower alkyl, phenyl-lower alkyl or a metal ion; and
n is 0 or 1.
U.S. Pat. No. 4,337,201 to Petrillo discloses phosphinylalkanoyl substituted prolines having the formula ##STR5## or a salt thereof, wherein R.sub.1 is alkyl, aryl, arylalkyl, cycloalkyl, or cycloalkylalkyl; one of R.sub.2 and R.sub.4 is ##STR6## and the other is hydrogen, alkyl aryalkyl or ##STR7## wherein X is hydrogen, alkyl or phenyl and Y is hydrogen, alkyl, phenyl or alkoxy, or together X and Y are --(CH.sub.2).sub.2 --, --(CH.sub.2).sub.3 --, --CH.dbd.CH--or ##STR8##
R.sub.3 is hydrogen or alkyl;
--R.sub.5 --COOR.sub.4 is ##STR9##
R.sub.6 is hydrogen, hydroxy, alkyl, halogen, azido, amino, cycloalkyl, aryl, arylalkyl, carbamoyloxy, N,N-dialkylcarbamoyloxy, or --Z--R9;
R.sub.7 and R'.sub.7 are the same and each is halogen or --Z--R.sub.10, or R.sub.7 and R'.sub.7 together are .dbd.O, --O--(CH.sub.2).sub.m --O--or --S--(CH.sub.2).sub.m --S--;
R.sub.8 is hydrogen and R'.sub.8 is phenyl, 2-hydroxyphenyl or 4-hydroxyphenyl or R.sub.8 and R'.sub.8 together are.dbd.O;
R.sub.9 is alkyl, aryl, arylalkyl, 1-- or 2-naphthyl, or biphenyl;
R.sub.10 is alkyl, aryl or arylalkyl;
Z is oxygen or sulfur;
n is 0 or 1; and
m is 1 or 2.
The Petrillo patent covers fosinopril ##STR10##
U.S. Pat. No. 4,432,971 to Karanewsky et al discloses phosphonamidate substituted amino or imino acids which are angiotensin converting enzyme inhibitors and salts thereof and have the formula ##STR11## wherein X is an imino or amino acid of the formula ##STR12##
R.sub.7 is hydrogen, lower alkyl, halogen, keto, hydroxy, ##STR13## azido, amino, ##STR14## a 1- or 2-naphthyl of the formula ##STR15## --(CH.sub.2).sub.m -cycloalkyl, ##STR16## --O-lower alkyl, ##STR17## a 1- or 2-naphthyloxy of the formula ##STR18## --S-lower alkyl, ##STR19## or a 1- or 2-naphthylthio of the formula ##STR20##
R.sub.8 is keto, halogen, ##STR21## --O-lower alkyl, a 1- or 2-naphthyloxy of the formula ##STR22## --S-lower alkyl, ##STR23## or a 1- or 2-naphthylthio of the formula ##STR24##
R.sub.9 is keto or ##STR25##
R.sub.10 is halogen or --Y--R.sub.16,
R.sub.11, R'.sub.11, R.sub.12 and R'.sub.12 are independently selected from hydrogen and lower alkyl or R'.sub.11, R.sub.12 and R'.sub.12 are hydrogen and R.sub.11 is ##STR26##
R.sub.13 is hydrogen, lower alkyl of 1 to 4 carbons, lower alkoxy of 1 to 4 carbons, lower alkylthio of 1 to 4 carbons, chloro, bromo, fluoro, trifluoromethyl, hydroxy, phenyl, phenoxy, phenylthio, or phenylmethyl.
R.sub.14 is hydrogen, lower alkyl of 1 to 4 carbons, lower alkoxy of 1 to 4 carbons, lower alkylthio of 1 to 4 carbons, chloro, bromo, fluoro, trifluoromethyl or hydroxy.
m is zero, one, two or three.
p is one, two or three provided that p is more than one only if R.sub.13 or R.sub.14 is hydrogen, methyl, methoxy, chloro or fluoro.
R.sub.15 is hydrogen or lower alkyl of 1 to 4 carbons.
Y is oxygen or sulfur.
R.sub.16 is lower alkyl of 1 to 4 carbons, ##STR27## or the R.sub.16 groups join to complete an unsubstituted 5- or 6-membered ring or said ring in which one or more of the carbons has a lower alkyl of 1 to 4 carbons or a di(lower alkyl of 1 to 4 carbons) substituent.
R.sub.4 is hydrogen, lower alkyl, cycloalkyl, or ##STR28##
R.sub.5 is hydrogen, lower alkyl, ##STR29##
r is an integer from 1 to 4,
R.sub.1 is hydrogen, lower alkyl or cycloalkyl.
R.sub.2 is hydrogen, lower alkyl, halo substituted lower alkyl, ##STR30##
or R.sub.1 and R.sub.2 taken together are --(CH.sub.2).sub.n -- wherein n is an integer from 2 or 4.
R.sub.3 and R.sub.6 are independently selected from hydrogen, lower alkyl, benzyl, benzhydryl, or ##STR31## wherein R.sub.17 is hydrogen, lower alkyl, or phenyl, and R.sub.18 is hydrogen, lower alkyl, lower alkoxy, phenyl, or R.sub.17 and R.sub.18 taken together are --(CH.sub.2).sub.2 --, --(CH.sub.2).sub.3 --, --CH.dbd.CH--, or ##STR32##
R.sub.19 is lower alkyl, benzyl, or phenethyl.
R.sub.20 is hydrogen, lower alkyl, benzyl or phenethyl.
R.sub.21 is alkyl of 1 to 10 carbons, ##STR33## wherein q is zero or an integer from 1 to 7 and R.sub.14, p and m are as defined above.
R.sub.22 and R.sub.23 are independently selected from hydrogen, lower alkyl, halo substituted lower alkyl, ##STR34## wherein m, R.sub.14, and p are as defined above.
U.S. Pat. No. 4,374,829 discloses carboxyalkyl dipeptide derivatives which are said to be angiotensin converting enzyme inhibitors and have the formula ##STR35## wherein R and R.sup.6 are the same or different and are hydroxy, lower alkoxy, lower alkenoxy, dilower alkylamino lower alkoxy (dimethylaminoethoxy), acylamino lower alkoxy (acetylamino-ethoxy), acyloxy lower alkoxy (pivaloyloxymethoxy), aryloxy, such as phenoxy, arylloweralkoxy, such as benzyloxy, substituted aryloxy or substituted arylloweralkoxy wherein the substituent is methyl, halo, methoxy, amino, loweralkylamino, diloweralkylamino, hydroxyamino, arylloweralkylamino such as benzylamino;
R.sup.1 is hydrogen, alkyl of from 1 to 20 carbon atoms which include branched and cyclic and unsaturated (such as allyl) alkyl groups, substituted loweralkyl wherein the substituent can be halo, hydroxy, lower alkoxy, aryloxy such as phenoxy, amino, diloweralkylamino, acylamino, such as acetamido and benzamido, arylamino, guanidino, imidazolyl, indolyl, mercapto, loweralkylthio, arylthio such as phenylthio, carboxy or carboxamido, carboloweralkoxy, aryl such as phenyl or naphthyl, substituted aryl such as phenyl wherein the substituent is lower alkyl, lower alkoxy or halo, arylloweralkyl, arylloweralkenyl, heteroaryllower alkyl or heteroaryllower alkenyl such as benzyl, styryl or indolyl ethyl, substituted arylloweralkyl, substituted arylloweralkenyl, substituted heteroaryllower alkyl, or substituted heteroaryllower alkenyl, wherein the substituents(s) is halo, dihalo, lower alkyl, hydroxy, lower alkoxy, amino, aminomethyl, acylamino (acetylamino or benzoylamino) diloweralkylamino, loweralkylamino, carboxyl, haloloweralkyl, cyano or sulfonamido; arylloweralkyl or heteroarylloweralkyl substituted on the alkyl portion by amino or acylamino (acetylamino or benzoylamino);
R.sup.2 and R.sup.7 are the same or different and are hydrogen or lower alkyl;
R.sup.3 is hydrogen, lower alkyl, phenyl lower alkyl, aminomethyl phenyl lower alkyl, hydroxy phenyl lower alkyl, hydroxy lower alkyl, acylamino lower alkyl (such as benzoylamino lower alkyl, acetylamino lower alkyl), amino lower alkyl, dimethylamino lower alkyl, halo lower alkyl, guanidino lower alkyl, imidazolyl lower alkyl, indolyl lower alkyl, mercapto lower alkyl, lower alkylthio lower alkyl;
R.sup.4 is hydrogen or lower alkyl;
R.sup.5 is hydrogen, lower alkyl, phenyl, phenyl lower alkyl, hydroxy phenyl lower alkyl, hydroxy lower alkyl, amino lower alkyl, guanidino lower alkyl, imidazolyl lower alkyl, indolyl lower alkyl, mercapto lower alkyl or lower alkylthio lower alkyl;
R.sup.4 and R.sup.5 may be connected together to form an alkylene bridge of from 2 to 4 carbon atoms, an alkylene bridge of from 2 to 3 carbon atoms and one sulfur atom, an alkylene bridge of from 3 to 4 carbon atoms containing a double bond or an alkylene bridge as above substituted with hydroxy, loweralkoxy, lower alkyl or dilower alkyl;
and the pharmaceutically acceptable salts thereof.
Example 41 of U.S. Pat. No. 4,374,829 describes the preparation of N-(1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline.
U.S. Pat. No. 4,452,790 to Karanewsky et al is directed to phosphonate substituted amino or imino acids and salts thereof having the formula ##STR36## wherein X is an imino or amino acid of the formula ##STR37##
R.sub.4 is hydrogen, lower alkyl, halogen, keto, hydroxy, ##STR38## azido, amino, ##STR39## a 1- or 2-naphthyl of the formula ##STR40## a 1- or 2-naphthyloxy of the formula ##STR41## or a 1- or 2-naphthylthio of the formula ##STR42##
R.sub.5 is keto, halogen, ##STR43## --O-lower alkyl, a 1- or 2-naphthyloxy of the formula ##STR44## --S-lower alkyl, ##STR45## or a 1- or 2-naphthylthio of the formula ##STR46##
R.sub.7 is keto or ##STR47##
Each R.sub.8 is independently halogen or --Y--R.sub.14.
R.sub.9, R.sub.9 ', R.sub.12 and R.sub.10 ' are independently selected from hydrogen and lower alkyl or R.sub.9 ', R.sub.10 and R.sub.10 ', are hydrogen and R.sub.9 is ##STR48##
R.sub.11 is hydrogen, lower alkyl of 1 to 4 carbons, lower alkoxy of 1 to 4 carbons, lower alkylthio of 1 to 4 carbons, chloro, bromo, fluoro, trifluoromethyl, hydroxy, phenyl, phenoxy, phenylthio, or phenylmethyl.
R.sub.12 is hydrogen, lower alkyl of 1 to 4 carbons, lower alkoxy of 1 to 4 carbons, lower alkylthio of 1 to 4 carbons, chloro, bromo, fluoro, trifluoromethyl or hydroxy.
m is zero, one, two or three.
p is one, two or three provided that p is more than one only if R.sub.11 or R.sub.12 is hydrogen, methyl, methoxy, chloro or fluoro.
R.sub.13 is hydrogen or lower alkyl of 1 to 4 carbons.
Y is oxygen or sulfur.
R.sub.14 is lower alkyl of 1 to 4 carbons, ##STR49## or the R.sub.14 groups join to complete an unsubstituted 5- or 6-membered ring or said ring in which one or more of the carbons has a lower alkyl of 1 to 4 carbons or a di(lower alkyl of 1 to 4 carbons) substituent.
R.sub.21 is hydrogen, lower alkyl, cycloalkyl, phenyl or ##STR50##
R.sub.22 is hydrogen, lower alkyl, ##STR51##
r is an integer from 1 to 4.
R.sub.1 is alkyl of 1 to 10 carbons, aminoalkyl, haloalkyl, ##STR52## wherein q is zero or an integer from 1 to 7 and R.sub.12 and p are as defined above.
R.sub.19 and R.sub.20 are independently selected from hydrogen, lower alkyl, halo substituted lower alkyl, ##STR53## wherein m, R.sub.11, and p are as defined above.
R.sub.2 is hydrogen, lower alkyl, halo substituted lower alkyl, ##STR54## wherein r is as defined above.
R.sub.3 and R.sub.6 are independently selected from hydrogen, lower alkyl, benzyl, alkali metal such as Li, Na or K, benzhydryl, or ##STR55## wherein R.sub.15 is hydrogen, lower alkyl, cycloalkyl or phenyl, and R.sub.16 is hydrogen, lower alkyl, lower alkoxy, phenyl, or R.sub.15 and R.sub.16 taken together are --(CH.sub.2).sub.2 --, --(CH.sub.2).sub.3 --, --CH.dbd.CH--, or ##STR56##
R.sub.17 is lower alkyl, benzyl, or phenethyl.
R.sub.18 is hydrogen, lower alkyl, benzyl or phenethyl.
This patent covers (S)-1-[6-amino-2-[[hydroxy(4-phenylbutyl)phosphinyl]oxy]-1-oxohexyl]-L-pro line (SQ 29, 852).
U.S. Pat. No. 4, 248,883 to Sawayame et al discloses 1-(3-mercapto-2-methylpropanoyl)-prolyl amino acid derivatives of the formula ##STR57## wherein R represents a hydrogen atom, a lower alkyl group, a phenyl-lower alkyl group or a substituted phenyl-lower alkyl group; R.sub.1 represents a hydrogen atom, R.sub.4 CO--, R.sub.5 S-- or ##STR58##
R.sub.2 represents a hydrogen atom or a lower alkyl group;
R.sub.3 represents a hydrogen atom, a phenyl group, a lower alkyl group, or a substituted lower alkyl group in which the substituent is hydroxy, phenyl-lower alkoxy, amino, guanidino, N-nitroguanidino, carboxyl, lower alkoxycarbonyl, phenyl-lower alkoxycarbonyl, carbamoyl, mercapto, lower alkylthio, phenyl, hydroxyphenyl, indolyl or imidazolyl; or R.sub.2 and R.sub.3 form a heterocyclic ring together with the nitrogen and carbon atoms to which they are respectively bonded; R.sub.4 represents a lower alkyl group, a lower alkoxy group, a phenyl group, a substituted phenyl group, a phenyl-lower alkyl group, a substituted phenyl-lower alkyl group, a phenyl-lower alkoxy group, a substituted phenyl-lower alkoxy group, a phenoxy group, or a substituted phenoxy group; R.sub.5 represents a lower alkyl group, a phenyl group, a substituted phenyl group, a phenyl-lower alkyl group, a substituted phenyl-lower alkyl group, ##STR59## or an amino(-carboxy)lower alkyl group; R.sub.6 represents a hydrogen atom or a lower alkyl group; R.sub.7 represents a lower alkyl group, a phenyl group or a substituted phenyl group; X represents an oxygen or sulfur atom; and the substituent in the substituted phenyl group is a halogen atom, a lower alkyl group, or a lower alkoxy group; and salts of said derivatives.
U.S. Pat. No. 4,316,906 to Ondetti et al discloses ether and thioether mercaptoacyl prolines of the formula ##STR60## wherein
the group X--R.sub.1 is located at the 3- or 4-position in the ring;
X is oxygen or sulfur;
R is hydrogen or lower alkyl;
R.sub.1 is lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, 1- or 2-adamantyl, aryl, substituted aryl, phenyl-lower alkylene or substituted phenyl-lower alkylene.
R.sub.2 and R.sub.3 are independently selected from hydrogen, lower alkyl, and trifluoromethyl;
R.sub.4 is hydrogen, R.sub.5 --CO-- or ##STR61##
R.sub.5 is lower alkyl, phenyl, phenyl-lower alkylene; substituted phenyl, or substituted phenyl-lower alkylene;
n is 0, 1 or 2; and salts thereof.
This Ondetti et al patent covers zofenopril